Salmonella's Molecular Mimics May Spark Arthritis, Study
Shows

By Marjorie CentofantiJHMI

Scientists at Johns Hopkins have uncovered an important link
between getting specific bacterial infections and developing
autoimmune diseases such as arthritis.

In a study reported in this month's edition of the journal
Nature Medicine, the researchers show clearly that
immune system cells that fight bacteria also can attack normal
cells carrying a specific mimic molecule--one that closely
resembles a bacterial protein.

Further, they show that as long as there's been a previous
bacterial infection, immune cells can attack "innocent bystander"
cells--body cells that bacteria have never infected. This occurs
when the cells are stressed by exposure to irradiation,
environmental toxins or the body's stress chemicals.

"We've found this evidence that the immune system can be
fooled, and it suggests subtle changes that could underlie many
autoimmune diseases," says Mark Soloski, an associate professor
in the School of Medicine, who led the research team. The study
also offers a starting place for scientists to investigate
environmental or genetic triggers to autoimmune diseases.

The team focused on infections by Salmonella, bacteria
well-known for food poisoning but also long-thought to trigger
arthritis in some people. "As many as 10 percent of those who get
Salmonella develop a 'reactive' kind of arthritis which lasts a
few weeks," Soloski says. "But a smaller, significant number of
those patients get a severe, debilitating type of arthritis
that's long-lasting."

To investigate bacteria/arthritis connections, the
scientists observed behavior of a typical bacteria-fighting
immune cell, the cytotoxic lymphocyte, as it approached infected
body cells. Cells invaded by bacteria normally give clear signals
that they're infected. "They display small pieces of bacterial
proteins on their surface that say, in effect, 'Hey, here's a
sick cell,'" Soloski says. Attracted by this protein "flag," CTLs
dock with the infected cells and trigger their rapid
self-destruction.

The Hopkins scientists first identified the protein "flag"
in mouse cells infected with Salmonella as one common to certain
bacteria associated with human arthritis, including Borrelia, the
cause of Lyme disease.

But they also found the bacterial "flag" was almost
identical to parts of a "universal housekeeping molecule" found
in humans, mice and all living organisms. This "housekeeping
molecule" helps proteins keep their shape.

When researchers artificially coaxed mouse body cells to
display the Salmonella "flag," the mouse CTLs would readily
attack them. But CTLs also went into attack mode if the cells
displayed a piece of the mouse's own housekeeping molecule or the
identical human version.

In a normal Salmonella infection in mice, Soloski says, "at
least half of the CTLs are stirred up to recognize the mouse's
own protein as well as the bacterial one. That's a huge immune
response." Based on the similarity of the setup in humans, he
adds, the response is likely the same. Now the scientists are
trying to find why and how this immune response translates into
arthritis in some mice and humans.

In a small side study, the team also found that normal,
uninfected body cells could be attacked by CTLs if the cells were
stressed in some way, such as being exposed to higher
temperature, radiation or general infection. "We don't know
what's going on here," says Soloski, "but it's a good place to
study other triggers of autoimmune diseases."

Other researchers from Hopkins were lead author Wei-Feng Lo,
Amy DeCloux, Amina S. Woods and Robert J. Cotter. The research
was funded by NIH grants and by an award from the Maryland
Chapter of The Arthritis Foundation.